Insulin dependent diabetes (IDDM) develops in several stages. Some people inherit genes which put them at high risk. From this group certain individuals develop immunologic damage to the insulin producing B-cell in the pancreas. Genetic and immunologic markers have been identified which in non-diabetic family members of an insulin dependent diabetic (IDD) are associated with impaired pancreatic B-cell function and an increased risk of developing clinical IDDM. It is unknown, however, whether these genetic and immunologic markers have similar pathophysiologic associations when they occur in the general population. It is also unknown whether immunologic damage can be subclinical and nonprogressive in some cases. Since 90% of all new cases of IDDM give no family history of diabetes, attempts to predict the development of new cases of IDDM will require a clear understanding of the natural history of IDDM in the general population. Recent advances in techniques for measuring genetic and immunologic markers along with the development of sensitive in vivo measures of pancreatic B-cell function have made the investigation of specific questions in the general population an exciting and realistic possibility. We propose to study 4,000 individuals aged 12-18 years, who have no family history of diabetes. We predict that the immune markers islet cell antibodies (ICA), insulin autoantibody (IAA) and antibodies to 64 kilodalton antigen (64KA) will occur more frequently in those who carry the genetic markers DQ3.2 and/or DQw2. We further predict that the presence of ICA, IAA and 64KA will be associated with impaired pancreatic B-cell function, that this will be detectable by changes in several in vivo measurements [loss of glucose potentiation of arginine stimulated insulin secretion, reduction in insulin response to intravenous glucose, increase in glycosylated hemoglobin (HbA1c)]. We predict that these changes will be more marked and more likely to be progressive when found in individuals who have ICA/IAA/64KA in association with DQ3.2/DQw2 than in those who do not carry those genetic markers. By developing a clearer understanding of the natural history of IDDM in the general population, it should be possible to apply preventive measures in a rational and timely manner in the future.